The present invention relates to the preparation of chenodeoxycholic acid, and, more particularly, to certain novel intermediates as well as to a novel process employing such intermediates in the preparation of chenodeoxycholic acid.
Chenodeoxycholic acid is one of the two primary bile acids in man and, in fact, is the key raw material in the ursodeoxy cholic acid synthetic pathway. Recently, it has attracted a great deal of attention from the pharmaceutical industry by virtue of its usefulness in the treatment of gallstones. More specifically, in clinical studies conducted with patients suffering from gallstones, it was observed that about 60% of the patients treated with chenodeoxycholic acid exhibited a reduction in the number of gallstones produced. Ursodeoxycholic acid, which as indicated above is a derivative of chenodeoxy-cholic acid, is also useful in the treatment of gallstones as well as for aiding the liver function generally.
Although recognized as a useful compound, the synthesis of chenodeoxycholic acid has been fraught with difficulties. Specifically, the structure of chenodeoxycholic acid is as follows: ##STR2## It is noted in the above formula that the compound has hydroxy groups at its number 3 and 7 positions. One of the problems which has been encountered in the synthesis of the above compound is that the typical starting reagent namely, 5.beta.-cholanic acid-3.alpha.,7.alpha.,12.alpha.-triol methyl ester has hydroxy groups at not only the number 3 and 7 positions, but also at the number 12 position and it is very difficult to selectively eliminate such number 12 hydroxy without also adversely affecting the desired number 3 and 7 hydroxy groups. This is especially true with respect to the differentiation between the hydroxy groups at the number 7 and 12 positions which are virtually indistinguishable in terms of their reactivity with most conventional oxidation agents.
The art has developed a number of synthetic processes in an attempt to differentiate among the various hydroxy groups. Thus, in the procedure described by Sato and Ikekawa in "Preparation of Chenodeoxychloic Acid", J. Organic Chemistry, Volume 24, pp. 1367-8 (September 1959), methyl cholate 3,7-diacetate was oxidized with Kiliani's reagent (a solution of 53 g of chromium trioxide and 80 g of concentrated sulfuric acid in 460 g of water) in acetone to the 12-oxo derivative. After conversion to the corresponding 12-thioketal with ethanedithiol, it was desulfurized successfully with Raney nickel to the acetate methyl ester of chenodeoxycholic acid. Subsequent hydrolysis of the acetate methyl ester yielded chenodeoxycholic acid of high purity.
Another process for producing chenodeoxycholic acid is set forth in Pharmazeutische Wirkstoffe, by Von A. Kleemann and J. Engel, Georg Thieme Verlag Stutgart pp. 181-182 (1982) wherein 5.beta.-cholanic acid-3.alpha.,7.alpha.,12.alpha.-triol methyl ester is formed from the corresponding carboxylic acid by reaction with methanol and sulfuric acid. The methyl ester is then reacted with acetic anhydride in the presence of pyridine to yield methyl cholate 3,7-diacetate. It is then necessary to selectively oxidize the hydroxy group at the number 12 while leaving the acetoxy groups at the number 3 and 7 positions intact. This is achieved by reacting the methyl cholate 3,7-diacetate with sodium dichromate and acetic acid to yield the 12-oxo derivative which, upon further reaction with hydrazine and HOCH.sub.2 --CH.sub.2 OH followed by HCl yields the desired chenodeoxycholic acid.
A number of disadvantages exist with the above-described synthetic routes. In the first place, the initial step of esterifying only the number 3 and 7 hydroxy groups but leaving the number 12 hydroxy intact, while theoretically attractive, has not proven completely satisfactory in practice in view the fact that some of the hydroxy groups at the number 12 position are indeed esterified. Such esterified groups, of course, will not react in the subsequent oxidation step. Furthermore, it is noted that even where esterification occurs as desired, i.e., only at the number 3 and 7 positions so that the number 7 hydroxy can be selectively oxidized, the removal of such ester group, especially at the number 6 carbon, is quite difficult to carry out in practice. Not surprisingly, in light of the undesirable side reactions which occur in the above-described synthetic processes, there will be present with the desired product a number of impurities which make it very difficult to obtain product crystals of high purity.
Perhaps the most significant disadvantage of the above processes concerns the chromium trioxide or the dichromates themselves, which are very dangerous to handle since they are both highly toxic and suspected carcinogens which, of course, must be kept isolated from workers and disposed of very carefully and with great cost.
Nonetheless, despite the environmental hazards and the costs associated with selective chromium dioxide and dichromate salts oxidation, the art continues to employ such technique as the preferred synthetic route in view of the lack of viable alternatives.